tbuckley/cabot-search huggingface dataset:
Abstract F2-2: Neutrophil elastase and anti-tumor effects
Authors: Lev Becker
Journal: Cancer Research (2023)

Abstract Cancer cell genetic variability and similarity to host cells have stymied development of broad anti-cancer therapeutics. Our innate immune system evolved to clear genetically diverse pathogens and limit host toxicity; however, whether/how innate immunity can produce similar effects in cancer is unknown. Here, we show that human, but not murine, neutrophils release catalytically active neutrophil elastase (ELANE) to kill many cancer cell types while sparing non-cancer cells. On a molecular level, ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively eradicate cancer cells. In pre-clinical models, ELANE attenuates primary tumor growth and produces a CD8+ T cell-mediated abscopal effect to attack distant metastases, therapeutic effects that are improved on by porcine pancreatic elastase, an ELANE homolog that better resists protease inhibitors in the tumor microenvironment. Altogether, our studies suggest that ELANE kills genetically diverse cancer cells with minimal toxicity to non-cancer cells, raising the possibility of developing it as a broad anti-cancer therapy. Citation Format: Lev Becker. Neutrophil elastase and anti-tumor effects [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr F2-2.
Abstract P2-06-01: Improving the health of women on Aromatase Inhibitors: A pilot controlled dietary and exercise intervention trial
Authors: Catherine L. Carpenter, Aashini K. Master, Olivia Julian, Dina Ben-Nissan, Michele Rakoff, Gail Thames, Zhaoping Li
Journal: Cancer Research (2023)

Abstract Background: In spite of aromatase inhibitors reducing risk of recurrence and mortality, painful side effects often cause women to discontinue use of the drug. Side effects of aromatase inhibitors include joint and muscle pain, loss of bone mineral density, and impairment of heart functioning. Discontinuation of aromatase inhibitors due to these side effects occur in up to 40% of breast cancer survivors, and consequently risks of recurrence and mortality increase. Objective: We developed two interventions designed to reduce inflammation, alleviate pain and stabilize bone mineral density. Methods: We are currently conducting a pilot parallel intervention trial that is targeted toward alleviating side effects from aromatase inhibitors through dietary and exercise controlled interventions lasting for three months. The dietary intervention is an anti-inflammatory Mediterranean diet designed to decrease inflammation and lessen joint and muscle pain. Participants randomized to the Mediterranean dietary intervention are exclusively consuming food provided by Territory Foods®, an outside food preparation and delivery service, local to Los Angeles. Our exercise intervention is designed to mobilize the joints, and strengthen and reduce bone loss. Participants are visiting the UCLA Kinross gym for three days per week and are undergoing tailored exercise sessions delivered from personal trainers following our bone strengthening intervention protocol. Anthropometric measures, muscle strength, DXA scanning of bone mineral density, peripheral arterial tonometry, pulse wave velocity and biomarkers of inflammation, bone turnover and heart functioning are conducted at baseline, mid- and end of intervention. Results: Our trial is targeted to accrue 20 participants. Thus far we enrolled six participants, with three participants completing the trial. Analysis is ongoing and preliminary results will be presented at the San Antonio Breast Cancer Symposium in December, 2022. Post intervention reports from participants have noted a reduction in pain symptoms, moderate weight loss and increase in muscle strength. Citation Format: Catherine L. Carpenter, Aashini K. Master, Olivia Julian, Dina Ben-Nissan, Michele Rakoff, Gail Thames, Zhaoping Li. Improving the health of women on Aromatase Inhibitors: A pilot controlled dietary and exercise intervention trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-01.
Abstract F3-2: Fasting and caloric restriction mimetics stimulate anticancer immunosurveillance
Authors: Guido Kroemer
Journal: Cancer Research (2023)

Abstract Fasting and caloric restriction induce metabolic and neuroendocrine changes that have major anti-inflammatory and immunostimulatory effects. Some of these effects are mediated by a raise of ketone bodies (such as 3-hydroxybutyrate) and a decrease in circulating insulin-like growth factor-1 (IGF1), meaning that administration of 3-hydroxybutyrate and pharmacological inhibition of IGF1 receptor can mimic some of the beneficial effects of fasting on anticancer immunosurveillance. "Caloric restriction mimetics" (CRMs) are small molecules that induce autophagy through the same pathways that are activated by fasting, including the reduction of cytoplasmic protein acetylation. We have accumulated evidence that CRMs can stimulate anticancer immunosurveillance either as single agents (for the prevention of malignant disease) or in combination with chemotherapy and/or immune checkpoint blockade (for the treatment of established cancers). In preclinical experiments, fasting and CRMs have also been used for the prevention or treatment of hormone-induced breast cancer, and these effects are coupled to an increase in the T lymphocyte-mediated anticancer immune response. We have developed an in vitro screening assay to identify novel pharmacological agents that act as CRMs. Such neo-CRMs can be successfully employed to improve anticancer immunosurveillance in preclinical experiments. Citation Format: Guido Kroemer. Fasting and caloric restriction mimetics stimulate anticancer immunosurveillance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr F3-2.
Abstract P2-24-07: Combination of complete estrogen receptor antagonist, OP-1250, and CDK4/6 inhibitors enhances tumor suppression and inhibition of cell cycle-related gene expression
Authors: Alison D. Parisian, Gopinath S. Palanisamy, Fabian Ortega, Judevin L. Sapugay, William J. Bodell, David Kulp, Peter Kushner, Cyrus Harmon
Journal: Cancer Research (2023)

Abstract OP-1250, a complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD), is currently in Phase I/II clinical trials for the treatment of estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. OP-1250 has previously demonstrated efficacy in both estrogen receptor 1 (ESR1) wild-type and Y537S mutant breast cancer xenograft models. Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are a standard first-line treatment for ER+ advanced or metastatic breast cancer in combination with endocrine therapy. To characterize OP-1250 efficacy in this setting, we explored the combination of OP-1250 with CDK4/6 inhibitors palbociclib and ribociclib in ER+/HER2- breast cancer preclinical models, and profiled the transcriptional changes associated with single agent and combination therapy. OP-1250 and CDK4/6 inhibitors were tested alone and in combination in ESR1 wild-type MCF7 and ESR1 Y537S mutant ST941 xenograft models. Higher doses of OP-1250 and either CDK4/6 inhibitor, when given as a monotherapy, suppress tumor growth and increase animal survival, while lower doses of the compounds display a modest or minimal effect on tumor growth or survival. In combination, lower doses of OP-1250 and either CDK4/6 inhibitor result in significantly greater tumor growth suppression (both xenograft models), tumor regression (MCF7) and animal survival (ST491) than each compound individually. RNA sequencing revealed substantially more gene expression changes with combination treatment than monotherapy. In particular, pathways associated with cell cycle progression displayed greater changes with combination treatment, similar to what was observed with a much higher dose of monotherapy. This study supports the clinical evaluation of OP-1250 in combination with CDK4/6 inhibitors (palbociclib or ribociclib) and provides additional context to mechanisms of combination efficacy. OP-1250 is currently being evaluated in a Phase Ib clinical trial in combination with palbociclib and a study including evaluation of the combination of OP-1250 with ribociclib is planned to initiate in Q3 2022. Citation Format: Alison D. Parisian, Gopinath S. Palanisamy, Fabian Ortega, Judevin L. Sapugay, William J. Bodell, David Kulp, Peter Kushner, Cyrus Harmon. Combination of complete estrogen receptor antagonist, OP-1250, and CDK4/6 inhibitors enhances tumor suppression and inhibition of cell cycle-related gene expression [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-07.
Abstract ED11-1: Hormone receptor positive breast cancer
Authors: Cynthia Ma
Journal: Cancer Research (2023)

Abstract Estrogen receptor (ER) positive breast cancer is a heterogeneous group of diseases. While the major goal of neoadjuvant treatment in patients with locally advanced disease is to downstage the cancer to facilitate resectability and breast-conserving surgery, there is increasing evidence that response in the neoadjuvant setting has prognostic implications in predicting long term relapse outcomes. However, questions remain as to strategies that optimize neoadjuvant treatment selection of endocrine therapy versus chemotherapy, and whether adjuvant therapy could be tailored based on treatment response in the neoadjuvant setting. In this lecture, we will discuss evolving data regarding pathologic and molecular characteristics of ER positive breast cancer that assist with treatment selection in the neoadjuvant setting and the potential role of pathologic and biomarker response to neoadjuvant endocrine therapy in tailoring adjuvant chemotherapy decisions. Citation Format: Cynthia Ma. Hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED11-1.
Abstract ED1-1: What are PROs and evidence for benefit?
Authors: Shoshana Rosenberg
Journal: Cancer Research (2023)

Abstract Patient-reported outcomes (PROs) are self-reported assessments provided directly by patients. PROs can be used for research, to tailor and improve clinical and supportive care, and for quality assessment purposes. It is well-established that PROs, rather than clinician evaluations, better capture the patient experience. Additionally, there is growing evidence supporting the routine incorporation of PROs into clinical practice. In particular, the use of PRO-based interventions is associated with improved symptom management, enhanced patient-provider communication, and better outcomes, including quality of life and survival, in patients with advanced cancer. Among patients in the post-active treatment and survivorship phase of care, PROs are critical in identifying and understanding late and long-term effects of treatment, identifying unmet needs, and determining if survivors are receiving appropriate follow-up care. There are also data in the survivorship setting demonstrating how PROs can predict other outcomes, such as adherence to aromatase inhibitors in breast cancer survivors. Careful consideration of age (e.g., pediatric vs. adult measures), race and ethnicity (e.g., was the measure validated in a diverse and representative population), language (e.g., was the measure validated in other languages), literacy level (e.g., was the measure written for individuals with low literacy levels), mode of delivery (e.g., paper vs. tablet), and participant burden (e.g., does the assessment take a reasonable amount of time) when selecting PROs is critical to ensure that the information learned is generalizable and that the benefit patients can gain through the incorporation of PROs into cancer care is equitable. Citation Format: Shoshana Rosenberg. What are PROs and evidence for benefit? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED1-1.
Abstract P2-16-02: TXNIP-dependent tumor suppressive pathways in breast cancer growth and progression
Authors: Jasvinder Singh, Bindeshwar sah, Liang Liu
Journal: Cancer Research (2023)

Abstract Thioredoxin-interacting protein (TXNIP) plays a critical role in glucose metabolism and redox signaling through negatively regulating thioredoxin activity. Over the past decade, TXNIP has emerged as a novel tumor suppressor in various cancer models. In search of the molecular targets mediating the anticancer effect of an epigenetic drug UNC0642, we found TXNIP to be consistently upregulated by UNC0642, which was coupled with significant suppression of MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo. TXNIP knockdown increased MDA-MB-231 cell proliferation and in vivo tumor growth and metastasis. In contrast, TXNIP-reconstitution in TXNIP-deficient HCC1954 breast cancer cells suppressed cell proliferation and migration that is coupled with increases in reactive oxygen species, strongly supporting TXNIP’s potent antitumor function. TXNIP-reconstitution also decreased mitochondrial respiration and glycolysis in HCC-1954 cells as determined by using the Agilent Seahorse XF Cell Energy assays. To understand the molecular targets through which TXNIP exerted its antitumor activity, we performed co-immunoprecipitation studies and proteomic analyses to identify TXNIP-interacting proteins in UNC0642-treated MDA-MB-231 cells. Besides thioredoxin, we identified peroxiredoxin-6 (PRDX6), another modulator of cellular redox signaling, as a major TXNIP-interacting protein. While Prdx6-knockout mice develop normally, PRDX6 is frequently upregulated in breast cancer patients that is significantly associated with aggressive tumor subtypes and poor overall survival. The mechanism underlying the role of PRDX6 in breast oncogenesis remains elusive. Our findings suggest that TXNIP might exert its antitumor activity through binding and inhibiting PRDX6 activity in breast cancer cells to alter ROS signaling, thus providing novel therapeutic targets and potential prognostic biomarkers for breast cancer patients. Citation Format: Jasvinder Singh, Bindeshwar sah, Liang Liu. TXNIP-dependent tumor suppressive pathways in breast cancer growth and progression [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-02.
Abstract GS5-12: Hypofractionated Radiotherapy in patients with Breast Cancer (HRBC): Acute toxicity data of a phase III randomized study
Authors: Budhi Singh Yadav, Divya Dahiya, Manish Gupta
Journal: Cancer Research (2023)

Abstract Background HRBC is a phase III randomized open label study of adjuvant radiotherapy in patients with breast cancer. In this study we compared a 3 weeks radiation schedule with 2 weeks. Materials and methods Patients with breast cancer, stage I-III, post mastectomy or after breast conservative surgery who needed adjuvant locoregional radiotherapy were randomized to 34Gy in 10 fractions over 2 weeks (study arm) or 35Gy in 15 fractions over 3 weeks to the chest wall and 40Gy/15#/3wks to breast and supraclavicular fossa (control arm). Boost dose when indicated was 8Gy/2# in both the arms. Patients were planned on simulator with 2 tangential fields to breast/chest wall and incident supraclavicular fossa field. Acute toxicity was assessed using a RTOG grading system. Assessment was carried out weekly during radiotherapy and at 4 weeks after treatment by the physician. Cosmetic outcome was assessed using Harvard/NSABP/RTOG scale. The toxicity between the two arms was compared using Fisher’s exact test. The trial was approved by institutional ethics committee. This trial is registered with ClinicalTrials.gov, number NCT04075058. Results This study included 1121 patients. Median follow up was 35 months (range 6-84 months). Mean age was 48 year (range 24-80 years). The patient characteristics were comparable between the two arms except for more mastectomies in the 3 week arm and more node positive patients in the 2 week arm. There were more oestrogen receptor positive tumors in the 3 week arm. Acute skin toxicities were comparable between the two arms. Grade 2 and 3 skin toxicity was 98(17%) and 82(15%); and 16(3%) and 10(2%) in the 3 week and 2 week arm (p=0.15), respectively. Cosmetic outcome was significantly better in 2 week arm 94% as compared to 90% in the 3 week arm (p=0.016). Conclusion The two radiation schedules were comparable in terms of acute skin toxicity. Cosmetic outcome was better in the 2 week schedule. Citation Format: Budhi Singh Yadav, Divya Dahiya, Manish Gupta. Hypofractionated Radiotherapy in patients with Breast Cancer (HRBC): Acute toxicity data of a phase III randomized study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-12.
Abstract P6-05-32: Does Aggregation Hide Place of Death Disparities for Asians with Breast Cancer?
Authors: Naveena Lall, Alexandra Noveihed, Qasim S. Hussaini, Amanda L. Blackford, Arjun Gupta, Ramy Sedhom
Journal: Cancer Research (2023)

Abstract Introduction: Place of death (PoD) studies are often used to motivate and monitor progress on health inequities for persons with cancer. It remains unclear whether aggregation of Asian race masks disparities in health equity for care at the end of life. Methods: De-identified death certificate data were obtained via the National Center for Health Statistics. All adult (&amp;gt;18 years of age) breast cancer deaths from 2018 to 2019 were included. Multinomial logistic regression was used to test for differences in place of death associated with sociodemographic variables. Results: From 2018 through 2019, 81,772 died from breast cancer in the United States. Overall, persons of Asian descent were less likely to die at home compared to White patients. Disaggregation noted significant differences in likelihood of hospice facility use. For example, Filipino race was approximately 5 times more likely to utilize hospice facilities (CI 3.764, 8.718; p&amp;lt; 0.001) compared to Whites, whereas Chinese race was significantly less likely (OR 0.49, 95% CI 0.307 to 0.627, p&amp;lt; 0.001). American Indian (OR 0.006), Asian Indian (OR 0.016), and Samoan (0.011) were the least likely to die in a nursing facility. While trends were overall similar when compared to White, Black and Hispanics, the likelihood of PoD among Asian subgroups were significantly different. Conclusion: Our data highlights notable differences in PoD only apparent with disaggregation of Asian race. While this study remains exploratory in nature, and reasons to explain these disparities are necessary, disaggregation of the Asian Pacific Island category is imperative to unmask disparities to improve health equity among all indigenous populations. Association Between Race and Place of Death for Patients with Breast Cancer Table 1. Number of deaths due to breast cancer in 2018 and 2019, by race. Odds ratios for the association between race and place of death from multinomial regression. Citation Format: Naveena Lall, Alexandra Noveihed, Qasim S. Hussaini, Amanda L. Blackford, Arjun Gupta, Ramy Sedhom. Does Aggregation Hide Place of Death Disparities for Asians with Breast Cancer? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-32.
Abstract P4-07-01: Overall survival with locoregional surgery in de novo metastatic breast cancer
Authors: Ren Chongxi, Sun Jianna, Kong Lingjun
Journal: Cancer Research (2023)

Abstract Background: Breast cancer remains the most frequent type of cancer in women, with de novo metastatic breast cancer (dnMBC) accounting for approximately 6-10% of patients. Advances in treatment of dnMBC have led to an increase in overall survival (OS), but the role of locoregional surgery remains unclear. Aim: To determine the value of locoregional surgery compared with no surgery on OS of women with dnMBC Settings and design: This study was designed as a randomized clinical study and was approved by the Ethics Committee of the Ethics Committee of Cangzhou Clinical College of Integrated Traditional Chinese and Western Medicine of Hebei Medical University (NO.20200212). Methods: Patient characteristics were previously reported in ASCO2022. Eighty-six patients with dnMBC were randomised to surgery of the primary tumor followed by systemic therapy (surgery group) or to primary systemic therapy without surgery (non-surgery group), by a computer generated block randomisation sequence. Randomisation was stratified by site of distant metastases, number of metastatic lesions, and molecular subtypes. Follow-up visits were conducted during treatment, monthly in first year, every 3 months thereafter. The primary endpoint was overall survival analysed by intention to treat. The stratified log-rank test and Cox proportional hazards model were used to compare OS between groups. The level for significance was set at p&amp;lt; 0.05. All analyses were performed with STATA 17. Results: Between Jan 3, 2019, and Mar 29, 2021, of the 103 women presenting with dnMBC, we randomly assigned 86 patients: 44 to surgery of the primary tumor followed by systemic therapy and 42 to primary systemic therapy without surgery. At data cut-off of Dec 1, 2021, median follow-up was 27 months with 44 deaths (surgery group n=21, non-surgery group n=23). The 2-year OS was 45.2% without and 52.3% with locoregional surgery (hazard ratio=0.59; 95% CI, 0.32 to 1.12; p = 0.11). The median OS was 25.5 months (95% CI, 23.52 to 29.38) in non-surgery group and 33 months (95% CI, 27.43 to 34.53) in surgery group. Conclusions: Our prospective randomized trial showed that compared with non-surgery counterparts, locoregional surgery does not improve OS of patients with dnMBC. Large, well-designed studies involving a large number of cases, multi-institution trials and longer follow-up are needed to verify the finding. Citation Format: Ren Chongxi, Sun Jianna, Kong Lingjun. Overall survival with locoregional surgery in de novo metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-01.